Ultrasound therapy system

ABSTRACT

In one embodiment of the present invention, a system for treating an occlusion within a patient&#39;s vasculature with ultrasonic energy comprises a catheter configured to be passed through the patient&#39;s vasculature such that a portion of the catheter is positioned at an intravascular treatment site. The system further comprises an ultrasound radiating member, an ultrasound signal generator configured to supply a drive signal to the ultrasound radiating member, an infusion pump configured to pump a therapeutic compound into the fluid delivery lumen so as to cause the therapeutic compound to be delivered to the treatment site and a controller configured to control the ultrasound signal generator and the infusion pump.

PRIORITY APPLICATION

This application is a divisional of U.S. patent application Ser. No.11/739,629, filed Apr. 24, 2007, which claims the benefit of U.S.Provisional Application 60/794,330 (filed Apr. 24, 2006) and U.S.Provisional Application 60/799,119 (filed May 9, 2006), the entirecontents of these applications are hereby incorporated by reference.

FIELD OF THE INVENTION

The present invention relates generally to treatment of vascularocclusions, and more specifically to treatment of vascular occlusionswith ultrasonic energy and a therapeutic compound having microbubbles.

BACKGROUND OF THE INVENTION

Several medical applications use ultrasonic energy. For example, U.S.Pat. Nos. 4,821,740, 4,953,565 and 5,007,438 disclose the use ofultrasonic energy to enhance the effect of various therapeuticcompounds. An ultrasonic catheter can be used to deliver ultrasonicenergy and a therapeutic compound to a treatment site within a patient'sbody. Such an ultrasonic catheter typically includes an ultrasoundassembly configured to generate ultrasonic energy and a fluid deliverylumen for delivering the therapeutic compound to the treatment site.

As taught in U.S. Pat. No. 6,001,069, ultrasonic catheters can be usedto treat human blood vessels that have become partially or completelyoccluded by plaque, thrombi, emboli or other substances that reduce theblood carrying capacity of the vessel. To remove or reduce theocclusion, the ultrasonic catheter is used to deliver solutionscontaining therapeutic compounds directly to the occlusion site.Ultrasonic energy generated by the ultrasound assembly enhances theeffect of the therapeutic compounds. Such a device can be used in thetreatment of diseases such as ischemic stroke, peripheral arterialocclusion or deep vein thrombosis. In such applications, the ultrasonicenergy enhances treatment of the occlusion with therapeutic compoundssuch as urokinase, tissue plasminogen activator (IPA″), recombinanttissue plasminogen activator (“rtPA”) and the like. Further informationon enhancing the effect of a therapeutic compound using ultrasonicenergy is provided in U.S. Pat. Nos. 5,318,014, 5,362,309, 5,474,531,5,628,728, 6,001,069 and 6,210,356.

SUMMARY OF THE INVENTION

Certain therapeutic compounds contain a plurality of microbubbleshaving, for example, a gas formed therein. The efficacy of a therapeuticcompound can be enhanced by the presence of the microbubbles containedtherein. The microbubbles act as a nucleus for cavitation, which canhelp promote the dissolution and removal of a vascular occlusion.Furthermore, the mechanical agitation caused motion of the microbubblescan be effective in mechanically breaking up clot material. Therefore,ultrasound catheter systems configured for use with amicrobubble-containing therapeutic compound have been developed.

In one embodiment of the present invention, a method of treating avascular occlusion located at a treatment site within a patient'svasculature comprises positioning an ultrasound catheter at thetreatment site. The method further comprises delivering a microbubblecompound from the ultrasound catheter to the vascular occlusion whileultrasound is off during a first treatment phase. The method furthercomprises pausing the delivery of the microbubble compound anddelivering ultrasonic energy and therapeutic compound or cooling fluidfrom the ultrasound catheter to the vascular occlusion during a secondtreatment phase while the delivery of microbubble compound remainspaused.

In one embodiment of the present invention, a method of treating avascular occlusion located at a treatment site within a patient'svasculature comprises passing an ultrasound catheter through thepatient's vasculature to the treatment site. The ultrasound catheterincludes at least one fluid delivery port. The method further comprisespositioning the ultrasound catheter at the treatment site such that theat least one fluid delivery port is positioned within the occlusion. Themethod further comprises infusing a microbubble therapeutic compoundfrom the ultrasound catheter into an internal portion of the occlusion.The method further comprises pausing delivery of the microbubbletherapeutic compound from the ultrasound catheter after a first quantityhas been infused into the occlusion. The method further comprisesdelivering ultrasonic energy and a therapeutic compound from theultrasound catheter into the infused microbubble therapeutic compound.The method further comprises repositioning the ultrasound catheter atthe treatment site. The method further comprises infusing a secondquantity of microbubble therapeutic compound from the ultrasoundcatheter to the treatment site after the ultrasonic energy is deliveredto the treatment site.

In one embodiment of the present invention, an ultrasound cathetersystem comprises an elongate tubular body having an ultrasound radiatingmember and a fluid delivery lumen positioned therein. The system furthercomprises a fluid reservoir that is hydraulically coupled to a proximalportion of the fluid delivery lumen. The fluid delivery reservoircontains a microbubble therapeutic compound. The system furthercomprises an infusion pump configured to pump the microbubbletherapeutic compound from the fluid reservoir into the fluid deliverylumen. The system further comprises control circuitry configured to sendelectrical activation power to the infusion pump and to the ultrasoundradiating member. The control circuitry is configured such that theinfusion pump and the ultrasound radiating member are not activatedsimultaneously.

BRIEF DESCRIPTION OF THE DRAWINGS

Example embodiments of the vascular occlusion treatment system areillustrated in the accompanying drawings, which are for illustrativepurposes only. The drawings comprise the following figures, in whichlike numerals indicate like parts.

FIG. 1 is a schematic illustration of an ultrasonic catheter configuredfor insertion into large vessels of the human body.

FIG. 2 is a cross-sectional view of the ultrasonic catheter of FIG. 1taken along line 2-2.

FIG. 3 is a schematic illustration of an elongate inner core configuredto be positioned within the central lumen of the catheter illustrated inFIG. 2.

FIG. 4 is a cross-sectional view of the elongate inner core of FIG. 3taken along line 4-4.

FIG. 5 is a schematic wiring diagram illustrating an example techniquefor electrically connecting five groups of ultrasound radiating membersto form an ultrasound assembly.

FIG. 6 is a schematic wiring diagram illustrating an example techniquefor electrically connecting one of the groups of FIG. 5.

FIG. 7A is a schematic illustration of the ultrasound assembly of FIG. 5housed within the inner core of FIG. 4.

FIG. 7B is a cross-sectional view of the ultrasound assembly of FIG. 7Ataken along line 7B-7B.

FIG. 7C is a cross-sectional view of the ultrasound assembly of FIG. 7Ataken along line 7C-7C.

FIG. 7D is a side view of an ultrasound assembly center wire twistedinto a helical configuration.

FIG. 8 illustrates the energy delivery section of the inner core of FIG.4 positioned within the energy delivery section of the tubular body ofFIG. 2.

FIG. 9 illustrates a wiring diagram for connecting a plurality oftemperature sensors with a common wire.

FIG. 10 is a block diagram of a feedback control system for use with anultrasonic catheter.

FIG. 11A is a side view of a treatment site.

FIG. 11B is a side view of the distal end of an ultrasonic catheterpositioned at the treatment site of FIG. 11A.

FIG. 11C is a cross-sectional view of the distal end of the ultrasoniccatheter of FIG. 11B positioned at the treatment site before atreatment.

FIG. 11D is a cross-sectional view of the distal end of the ultrasoniccatheter of FIG. 110, wherein an inner core has been inserted into thetubular body to perform a treatment.

FIG. 12A is a cross-sectional view of a distal end of an ultrasoniccatheter configured for use within small vessels of a patient'svasculature.

FIG. 12B is a cross-sectional view of the ultrasonic catheter of FIG.12A taken through line 12B-12B.

FIG. 13 is a cross-sectional view of an ultrasound radiating memberseparated from a delivery lumen by a chamber.

FIG. 14 is a cross-sectional view of an example technique for applyingultrasonic energy to an infused microbubble therapeutic compound.

FIG. 15 is a schematic illustration of selected components of an examplesystem that is capable of using a single controller to alternativelydeliver ultrasonic energy and a microbubble therapeutic compound to anintravascular treatment site.

FIG. 16A illustrates a laser patterned cavitation promoting surface.

FIG. 16B illustrates a close up of a cavitation promoting surface.

FIG. 17 is a graph showing the relative noise enhancement versus timeduring a 3.33-second snapshot obtained at time zero in a 30-minuteultrasound exposure. Each trace is an average over 10 snapshots.

FIG. 18 is a graph showing the relative subharmonic enhancement versustime during a 3.33-second snapshot obtained at time zero in a 30-minuteultrasound exposure. Each trace is an average over 10 snapshots.

FIG. 19A is a graph showing the maximum noise enhancement per snapshotillustrated as a function of ultrasound exposure time. Each pointcorresponds to an average of 10 snapshots.

FIG. 19B is a graph showing a comparison of max{RNE} for the snapshottaken at time zero (0 min) and the average max{RNE} for snapshotsobtained during the remainder of the 30-minute exposure. Error barsindicate standard deviation.

FIG. 20A is a graph showing the average subharmonic enhancement persnapshot illustrated as a function of ultrasound exposure time. Eachpoint corresponds to an average of 10 snapshots.

FIG. 20B is a graph showing a comparison of <RSE> for the snapshot takenat time zero and the average <RSE> for snapshots obtained during theremainder of the 30-minute exposure. Error bars indicate standarddeviation.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

As set forth above, methods and apparatuses have been developed thatallow a vascular occlusion to be treated using both ultrasonic energyand a therapeutic compound having a controlled temperature. Disclosedherein are several example embodiments of ultrasonic catheters that canbe used to enhance the efficacy of therapeutic compounds at a treatmentsite within a patient's body.

Introduction.

As used herein, the term “therapeutic compound” refers broadly, withoutlimitation, and in addition to its ordinary meaning, to a drug,medicament, dissolution compound, genetic material, neuroprotectioncompounds or any other substance capable of effecting physiologicalfunctions. Additionally, a mixture includes substances such as these isalso encompassed within this definition of “therapeutic compound”.Examples of therapeutic compounds include thrombolytic compounds,anti-thrombosis compounds, and other compounds used in the treatment ofvascular occlusions, including compounds intended to prevent or reduceclot formation. In applications where human blood vessels that havebecome partially or completely occluded by plaque, thrombi, emboli orother substances that reduce the blood carrying capacity of a vessel,example therapeutic compounds include, but are not limited to, heparin,urokinase, streptokinase, tPA, rtPA and BB-10153 (manufactured byBritish Biotech, Oxford, UK).

As used herein, the terms “ultrasonic energy”, “ultrasound” and“ultrasonic” refer broadly, without limitation, and in addition to theirordinary meaning, to mechanical energy transferred through longitudinalpressure or compression waves. Ultrasonic energy can be emitted ascontinuous or pulsed waves, depending on the parameters of a particularapplication. Additionally, ultrasonic energy can be emitted in waveformshaving various shapes, such as sinusoidal waves, triangle waves, squarewaves, or other wave forms. Ultrasonic energy includes sound waves. Incertain embodiments, the ultrasonic energy referred to herein has afrequency between about 20 kHz and about 20 MHz. For example, in oneembodiment, the ultrasonic energy has a frequency between about 500 kHzand about 20 MHz. In another embodiment, the ultrasonic energy has afrequency between about 1 MHz and about 3 MHz. In yet anotherembodiment, the ultrasonic energy has a frequency of about 2 MHz. Incertain embodiments described herein, the average acoustic power of theultrasonic energy is between about 0.01 watts and 300 watts. In oneembodiment, the average acoustic power is about 15 watts.

As used herein, the term “ultrasound radiating member” refers broadly,without limitation, and in addition to its ordinary meaning, to anyapparatus capable of producing ultrasonic energy. An ultrasonictransducer, which converts electrical energy into ultrasonic energy, isan example of an ultrasound radiating member. An example ultrasonictransducer capable of generating ultrasonic energy from electricalenergy is a piezoelectric ceramic oscillator. Piezoelectric ceramicstypically comprise a crystalline material, such as quartz, that changesshape when an electrical current is applied to the material. This changein shape, made oscillatory by an oscillating driving signal, createsultrasonic sound waves. In other embodiments, ultrasonic energy can begenerated by an ultrasonic transducer that is remote from the ultrasoundradiating member, and the ultrasonic energy can be transmitted, via, forexample, a wire that is coupled to the ultrasound radiating member.

In certain applications, the ultrasonic energy itself provides atherapeutic effect to the patient. Examples of such therapeutic effectsinclude preventing or reducing stenosis and/or restenosis; tissueablation, abrasion or disruption; promoting temporary or permanentphysiological changes in intracellular or intercellular structures; andrupturing micro-balloons or micro-bubbles for therapeutic compounddelivery. Further information about such methods can be found in U.S.Pat. Nos. 5,261,291 and 5,431,663.

The ultrasonic catheters described herein can be configured forapplication of ultrasonic energy over a substantial length of a bodylumen, such as, for example, the larger vessels located in the leg. Inother embodiments, the ultrasonic catheters described herein can beconfigured to be inserted into the small cerebral vessels, in solidtissues, in duct systems and in body cavities. In other embodiments,treatment with the ultrasonic catheter is performed outside the vascularsystem, such as within or at a tumor, in which the treatment isconfigured to kill malignant tissues by enhancing the delivery of acancer drug to the tumor. Additional embodiments that can be combinedwith certain features and aspects of the embodiments described hereinare described in U.S. patent application Ser. No. 10/291,891, filed 7Nov. 2002, the entire disclosure of which is hereby incorporated hereinby reference.

Overview of a Large Vessel Ultrasonic Catheter.

FIG. 1 schematically illustrates an ultrasonic catheter 10 configuredfor use in the large vessels of a patient's anatomy. For example, theultrasonic catheter 10 illustrated in FIG. 1 can be used to treat longsegment peripheral arterial occlusions, such as those in the vascularsystem of the leg.

As illustrated in FIG. 1, the ultrasonic catheter 10 generally includesa multi-component, elongate flexible tubular body 12 having a proximalregion 14 and a distal region 15. The tubular body 12 includes aflexible energy delivery section 18 located in the distal region 15. Thetubular body 12 and other components of the catheter 10 can bemanufactured in accordance with a variety of techniques known to anordinarily skilled artisan. Suitable materials and dimensions can bereadily selected based on the natural and anatomical dimensions of thetreatment site and on the desired percutaneous access site.

For example, in an example embodiment, the tubular body proximal region14 comprises a material that has sufficient flexibility, kinkresistance, rigidity and structural support to push the energy deliverysection 18 through the patient's vasculature to a treatment site.Examples of such materials include, but are not limited to, extrudedpolytetrafluoroethylene (“PTFE”), polyethylenes (“PE”), polyamides andother similar materials. In certain embodiments, the tubular bodyproximal region 14 is reinforced by braiding, mesh or otherconstructions to provide increased kink resistance and ability to bepushed. For example, nickel titanium or stainless steel wires can beplaced along or incorporated into the tubular body 12 to reduce kinking.

For example, in an embodiment configured for treating thrombus in thearteries of the leg, the tubular body 12 has an outside diameter betweenabout 0.060 inches and about 0.075 inches. In another embodiment, thetubular body 12 has an outside diameter of about 0.071 inches. Incertain embodiments, the tubular body 12 has an axial length ofapproximately 105 centimeters, although other lengths can be used inother applications.

In an example embodiment, the tubular body energy delivery section 18comprises a material that is thinner than the material comprising thetubular body proximal region 14. In another example embodiment, thetubular body energy delivery section 18 comprises a material that has agreater acoustic transparency than the material comprising the tubularbody proximal region 14. Thinner materials generally have greateracoustic transparency than thicker materials. Suitable materials for theenergy delivery section 18 include, but are not limited to, high or lowdensity polyethylenes, urethanes, nylons, and the like. In certainmodified embodiments, the energy delivery section 18 comprises the samematerial or a material of the same thickness as the proximal region 18.

In an example embodiment, the tubular body 12 is divided into at leastthree sections of varying stiffness. The first section, which includesthe proximal region 14, has a relatively higher stiffness. The secondsection, which is located in an intermediate region between the proximalregion 14 and the distal region 15, has a relatively lower stiffness.This configuration further facilitates movement and placement of thecatheter 10. The third section, which includes the energy deliverysection 18, has a relatively lower stiffness than the second section inspite of the presence of ultrasound radiating members which can bepositioned therein.

FIG. 2 illustrates a cross section of the tubular body 12 taken alongline 2-2 in FIG. 1. In the embodiment illustrated in FIG. 2, three fluiddelivery lumens 30 are incorporated into the tubular body 12. In otherembodiments, more or fewer fluid delivery lumens can be incorporatedinto the tubular body 12. In such embodiments, the arrangement of thefluid delivery lumens 30 provides a hollow central lumen 51 passingthrough the tubular body 12. The cross-section of the tubular body 12,as illustrated in FIG. 2, is substantially constant along the length ofthe catheter 10. Thus, in such embodiments, substantially the samecross-section is present in both the proximal region 14 and the distalregion 15 of the tubular body 12, including the energy delivery section18.

In certain embodiments, the central lumen 51 has a minimum diametergreater than about 0.030 inches. In another embodiment, the centrallumen 51 has a minimum diameter greater than about 0.037 inches. In anexample embodiment, the fluid delivery lumens 30 have dimensions ofabout 0.026 inches wide by about 0.0075 inches high, although otherdimensions can be used in other embodiments.

In an example embodiment, the central lumen 51 extends through thelength of the tubular body 12. As illustrated in FIG. 1, the centrallumen 51 has a distal exit port 29 and a proximal access port 31. Theproximal access port 31 forms part of the backend hub 33, which isattached to the tubular body proximal region 14. In such embodiments,the backend hub also includes a cooling fluid fitting 46, which ishydraulically connected to the central lumen 51. In such embodiments,the backend hub 33 also includes a therapeutic compound inlet port 32,which is hydraulically coupled to the fluid delivery lumens 30, andwhich can also be hydraulically coupled to a source of therapeuticcompound via a hub such as a Luer fitting.

The central lumen 51 is configured to receive an elongate inner core 34,an example embodiment of which is illustrated in FIG. 3. In suchembodiments, the elongate inner core 34 includes a proximal region 36and a distal region 38. A proximal hub 37 is fitted on one end of theinner core proximal region 36. One or more ultrasound radiating members40 are positioned within an inner core energy delivery section 41 thatis located within the distal region 38. The ultrasound radiating members40 form an ultrasound assembly 42, which will be described in greaterdetail below.

As shown in the cross-section illustrated in FIG. 4, which is takenalong lines 4-4 in FIG. 3, in an example embodiment, the inner core 34has a cylindrical shape, with an outer diameter that permits the innercore 34 to be inserted into the central lumen 51 of the tubular body 12via the proximal access port 31. Suitable outer diameters of the innercore 34 include, but are not limited to, between about 0.010 inches andabout 0.100 inches. In another embodiment, the outer diameter of theinner core 34 is between about 0.020 inches and about 0.080 inches. Inyet another embodiment, the inner core 34 has an outer diameter of about0.035 inches.

Still referring to FIG. 4, the inner core 34 includes a cylindricalouter body 35 that houses the ultrasound assembly 42. The ultrasoundassembly 42 includes wiring and ultrasound radiating members, describedin greater detail in FIGS. 5 through 7D, such that the ultrasoundassembly 42 is capable of radiating ultrasonic energy from the energydelivery section 41 of the inner core 34. The ultrasound assembly 42 iselectrically connected to the backend hub 33, where the inner core 34can be connected to a control system 100 via cable 45 (illustrated inFIG. 1). In an example embodiment, an electrically insulating pottingmaterial 43 fills the inner core 34, surrounding the ultrasound assembly42, thus reducing or preventing movement of the ultrasound assembly 42with respect to the outer body 35. In one embodiment, the thickness ofthe outer body 35 is between about 0.0002 inches and 0.010 inches. Inanother embodiment, the thickness of the outer body 35 is between about0.0002 inches and 0.005 inches. In yet another embodiment, the thicknessof the outer body 35 is about 0.0005 inches.

In an example embodiment, the ultrasound assembly 42 includes aplurality of ultrasound radiating members 40 that are divided into oneor more groups. For example, FIGS. 5 and 6 are schematic wiring diagramsillustrating one technique for connecting five groups of ultrasoundradiating members 40 to form the ultrasound assembly 42. As illustratedin FIG. 5, the ultrasound assembly 42 comprises five groups G1, G2, G3,G4, G5 of ultrasound radiating members 40 that are electricallyconnected to each other. The five groups are also electrically connectedto the control system 100.

Still referring to FIG. 5, in an example embodiment, the controlcircuitry 100 includes a voltage source 102 having a positive terminal104 and a negative terminal 106. The negative terminal 106 is connectedto common wire 108, which connects the five groups G1-G5 of ultrasoundradiating members 40 in series. The positive terminal 104 is connectedto a plurality of lead wires 110, which each connect to one of the fivegroups G1-G5 of ultrasound radiating members 40. Thus, under thisconfiguration, each of the five groups G1-G5, one of which isillustrated in FIG. 6, is connected to the positive terminal 104 via oneof the lead wires 110, and to the negative terminal 106 via the commonwire 108.

Referring now to FIG. 6, each group G1-G5 includes a plurality ofultrasound radiating members 40. Each of the ultrasound radiatingmembers 40 is electrically connected to the common wire 108 and to thelead wire 110 via a positive contact wires 112. Thus, when wired asillustrated, a substantially constant voltage difference will be appliedto each ultrasound radiating member 40 in the group. Although the groupillustrated in FIG. 6 includes twelve ultrasound radiating members 40,in other embodiments, more or fewer ultrasound radiating members 40 canbe included in the group. Likewise, more or fewer than five groups canbe included within the ultrasound assembly 42 illustrated in FIG. 5.

FIG. 7A illustrates an example technique for arranging the components ofthe ultrasound assembly 42 (as schematically illustrated in FIG. 5) intothe inner core 34 (as schematically illustrated in FIG. 4). FIG. 7A is across-sectional view of the ultrasound assembly 42 taken within group G1in FIG. 5, as indicated by the presence of four lead wires 110. Forexample, if a cross-sectional view of the ultrasound assembly 42 wastaken within group G4 in FIG. 5, only one lead wire 110 would be present(that is, the one lead wire connecting group G5).

In the example embodiment illustrated in FIG. 7A, the common wire 108includes an elongate, flat piece of electrically conductive material inelectrical contact with a pair of ultrasound radiating members 40. Eachof the ultrasound radiating members 40 is also in electrical contactwith a positive contact wire 112. Because the common wire 108 isconnected to the negative terminal 106, and the positive contact wire112 is connected to the positive terminal 104, a voltage difference canbe created across each ultrasound radiating member 40. In suchembodiments, lead wires 110 are separated from the other components ofthe ultrasound assembly 42, thus preventing interference with theoperation of the ultrasound radiating members 40 as described above. Forexample, in an example embodiment, the inner core 34 is filled with aninsulating potting material 43, thus deterring unwanted electricalcontact between the various components of the ultrasound assembly 42.

FIGS. 7B and 7C illustrate cross sectional views of the inner core 34 ofFIG. 7A taken along lines 7B-7B and 7C-7C, respectively. As illustratedin FIG. 7B, the ultrasound radiating members 40 are mounted in pairsalong the common wire 108. The ultrasound radiating members 40 areconnected by positive contact wires 112, such that substantially thesame voltage is applied to each ultrasound radiating member 40. Asillustrated in FIG. 7C, the common wire 108 includes wide regions 108Wupon which the ultrasound radiating members 40 can be mounted, thusreducing the likelihood that the paired ultrasound radiating members 40will short together. In certain embodiments, outside the wide regions108W, the common wire 108 can have a more conventional, rounded wireshape.

In a modified embodiment, such as illustrated in FIG. 7D, the commonwire 108 is twisted to form a helical shape before being fixed withinthe inner core 34. In such embodiments, the ultrasound radiating members40 are oriented in a plurality of radial directions, thus enhancing theradial uniformity of the resulting ultrasonic energy field.

The wiring arrangement described above can be modified to allow eachgroup G1, G2, G3, G4, G5 to be independently powered. Specifically, byproviding a separate power source within the control system 100 for eachgroup, each group can be individually turned on or off, or can be drivenat an individualized power level. This advantageously allows thedelivery of ultrasonic energy to be “turned off” in regions of thetreatment site where treatment is complete, thus preventing deleteriousor unnecessary ultrasonic energy to be applied to the patient.

The embodiments described above, and illustrated in FIGS. 5 through 7,include a plurality of ultrasound radiating members grouped spatially.That is, in such embodiments, the ultrasound radiating members within acertain group are positioned adjacent to each other, such that when asingle group is activated, ultrasonic energy is delivered from a certainlength of the ultrasound assembly. However, in modified embodiments, theultrasound radiating members of a certain group may be spaced apart fromeach other, such that the ultrasound radiating members within a certaingroup are not positioned adjacent to each other. In such embodiments,when a single group is activated, ultrasonic energy can be deliveredfrom a larger, spaced apart portion of the ultrasound assembly. Suchmodified embodiments can be advantageous in applications where a lessfocussed, more diffuse ultrasonic energy field is to be delivered to thetreatment site.

In an example embodiment, the ultrasound radiating members 40 compriserectangular lead zirconate titanate (“PZT”) ultrasound transducers thathave dimensions of about 0.017 inches by about 0.010 inches by about0.080 inches. In other embodiments, other configurations and dimensionscan be used. For example, disc-shaped ultrasound radiating members 40can be used in other embodiments. In an example embodiment, the commonwire 108 comprises copper, and is about 0.005 inches thick, althoughother electrically conductive materials and other dimensions can be usedin other embodiments. In an example embodiment, lead wires 110 are 36gauge electrical conductors, and positive contact wires 112 are 42 gaugeelectrical conductors. However, other wire gauges can be used in otherembodiments.

As described above, suitable frequencies for the ultrasound radiatingmembers 40 include, but are not limited to, from about 20 kHz to about20 MHz. In one embodiment, the frequency is between about 500 kHz andabout 20 MHz, and in another embodiment the frequency is between about 1MHz and about 3 MHz. In yet another embodiment, the ultrasound radiatingmembers 40 are operated with a frequency of about 2 MHz.

FIG. 8 illustrates the inner core 34 positioned within the tubular body12. Details of the ultrasound assembly 42, provided in FIG. 7A, areomitted for clarity. As described above, the inner core 34 can be slidwithin the central lumen 51 of the tubular body 12, thereby allowing theinner core energy delivery section 41 to be positioned within thetubular body energy delivery section 18. For example, in an exampleembodiment, the materials comprising the inner core energy deliverysection 41, the tubular body energy delivery section 18, and the pottingmaterial 43 all comprise materials having a similar acoustic impedance,thereby minimizing ultrasonic energy losses across material interfaces.

FIG. 8 further illustrates placement of fluid delivery ports 58 withinthe tubular body energy delivery section 18. As illustrated, holes orslits are formed from the fluid delivery lumen 30 through the tubularbody 12, thereby permitting fluid flow from the fluid delivery lumen 30to the treatment site. A plurality of fluid delivery ports 58 can bepositioned axially along the tubular body 12. Thus, a source oftherapeutic compound coupled to the inlet port 32 provides a hydraulicpressure which drives the therapeutic compound through the fluiddelivery lumens 30 and out the fluid delivery ports 58.

By spacing the fluid delivery lumens 30 around the circumference of thetubular body 12 substantially evenly, as illustrated in FIG. 8, asubstantially uniform flow of therapeutic compound around thecircumference of the tubular body 12 can be achieved. Additionally, thesize, location and geometry of the fluid delivery ports 58 can beselected to provide uniform fluid flow from the fluid delivery ports 30to the treatment site. For example, in one embodiment, fluid deliveryports closer to the proximal region of the energy delivery section 18have smaller diameters than fluid delivery ports closer to the distalregion of the energy delivery section 18, thereby allowing uniformdelivery of therapeutic compound in the energy delivery section.

For example, in one embodiment in which the fluid delivery ports 58 havesimilar sizes along the length of the tubular body 12, the fluiddelivery ports 58 have a diameter between about 0.0005 inches to about0.0050 inches. In another embodiment in which the size of the fluiddelivery ports 58 changes along the length of the tubular body 12, thefluid delivery ports 58 have a diameter between about 0.001 inches toabout 0.005 inches in the proximal region of the energy delivery section18, and between about 0.005 inches to about 0.0020 inches in the distalregion of the energy delivery section 18. The increase in size betweenadjacent fluid delivery ports 58 depends on a variety of factors,including the material comprising the tubular body 12, and on the sizeof the fluid delivery lumen 30. The fluid delivery ports 58 can becreated in the tubular body 12 by punching, drilling, burning orablating (such as with a laser), or by other suitable methods.Therapeutic compound flow along the length of the tubular body 12 canalso be increased by increasing the density of the fluid delivery ports58 toward the distal region of the energy delivery section.

In certain applications, a spatially nonuniform flow of therapeuticcompound from the fluid delivery ports 58 to the treatment site is to beprovided. In such applications, the size, location and geometry of thefluid delivery ports 58 can be selected to provide such nonuniform fluidflow.

Referring still to FIG. 8, placement of the inner core 34 within thetubular body 12 further defines cooling fluid lumens 44. Cooling fluidlumens 44 are formed between an outer surface 39 of the inner core 34and an inner surface 16 of the tubular body 12. In certain embodiments,a cooling fluid is introduced through the proximal access port 31 suchthat cooling fluid flows through cooling fluid lumens 44 and out of thecatheter 10 through distal exit port 29 (see FIG. 1). In an exampleembodiment, the cooling fluid lumens 44 are substantially evenly spacedaround the circumference of the tubular body 12 (that is, atapproximately 120° increments for a three-lumen configuration), therebyproviding substantially uniform cooling fluid flow over the inner core34. Such a configuration advantageously removes thermal energy from thetreatment site. As will be explained below, the flow rate of the coolingfluid and the power to the ultrasound assembly 42 can be adjusted tomaintain the temperature of the inner core energy delivery section 41,or of the treatment site generally, within a desired range.

In an example embodiment, the inner core 34 can be rotated or movedwithin the tubular body 12. Specifically, movement of the inner core 34can be accomplished by maneuvering the proximal hub 37 while holding thebackend hub 33 stationary. The inner core outer body 35 is at leastpartially constructed from a material that provides enough structuralsupport to permit movement of the inner core 34 within the tubular body12 without kinking of the tubular body 12. Additionally, in an exampleembodiment, the inner core outer body 35 comprises a material having theability to transmit torque. Suitable materials for the inner core outerbody 35 include, but are not limited to, polyimides, polyesters,polyurethanes, thermoplastic elastomers and braided polyimides.

In an example embodiment, the fluid delivery lumens 30 and the coolingfluid lumens 44 are open at the distal end of the tubular body 12,thereby allowing the therapeutic compound and the cooling fluid to passinto the patient's vasculature at the distal exit port 29. In a modifiedembodiment, the fluid delivery lumens 30 can be selectively occluded atthe distal end of the tubular body 12, thereby providing additionalhydraulic pressure to drive the therapeutic compound out of the fluiddelivery ports 58. In either configuration, the inner core 34 can beprevented from passing through the distal exit port 29 by providing theinner core 34 with a length that is less than the length of the tubularbody 12. In other embodiments, a protrusion is formed within the tubularbody 12 in the distal region 15, thereby preventing the inner core 34from passing through the distal exit port 29.

In other embodiments, the catheter 10 includes an occlusion devicepositioned at the distal exit port 29. In such embodiments, theocclusion device has a reduced inner diameter that can accommodate aguidewire, but that is less than the inner diameter of the central lumen51. Thus, the inner core 34 is prevented from extending past theocclusion device and out the distal exit port 29. For example, suitableinner diameters for the occlusion device include, but are not limitedto, between about 0.005 inches and about 0.050 inches. In otherembodiments, the occlusion device has a closed end, thus preventingcooling fluid from leaving the catheter 10, and instead recirculating tothe tubular body proximal region 14. These and other cooling fluid flowconfigurations permit the power provided to the ultrasound assembly 42to be increased in proportion to the cooling fluid flow rate.Additionally, certain cooling fluid flow configurations can reduceexposure of the patient's body to cooling fluids.

In an example embodiment, such as illustrated in FIG. 8, the tubularbody 12 includes one or more temperature sensors 20 that are positionedwithin the energy delivery section 18. In such embodiments, the tubularbody proximal region 14 includes a temperature sensor lead which can beincorporated into cable 45 (illustrated in FIG. 1). Suitable temperaturesensors include, but are not limited to, temperature sensing diodes,thermistors, thermocouples, resistance temperature detectors (“RTDs”)and fiber optic temperature sensors which use thermalchromic liquidcrystals. Suitable temperature sensor 20 geometries include, but are notlimited to, a point, a patch or a stripe. The temperature sensors 20 canbe positioned within one or more of the fluid delivery lumens 30, and/orwithin one or more of the cooling fluid lumens 44.

FIG. 9 illustrates an example embodiment for electrically connecting thetemperature sensors 20. In such embodiments, each temperature sensor 20is coupled to a common wire 61 and is associated with an individualreturn wire 62. Accordingly, n+1 wires are passed through the tubularbody 12 to independently sense the temperature at n temperature sensors20. The temperature at a selected temperature sensor 20 can bedetermined by closing a switch 64 to complete a circuit between thereturn wire 62 associated with the selected thermocouple and the commonwire 61. In embodiments wherein the temperature sensors 20 arethermocouples, the temperature can be calculated from the voltage in thecircuit using, for example, a sensing circuit 63, which can be locatedwithin the external control circuitry 100.

In other embodiments, the temperature sensors 20 can be independentlywired. In such embodiments, 2n wires are passed through the tubular body12 to independently sense the temperature at n temperature sensors 20.In still other embodiments, the flexibility of the tubular body 12 canbe improved by using fiber optic based temperature sensors 20. In suchembodiments, flexibility can be improved because only n fiber opticmembers are used to sense the temperature at n independent temperaturesensors 20.

FIG. 10 schematically illustrates one embodiment of a feedback controlsystem 68 that can be used with the catheter 10. The feedback controlsystem 68 can be integrated into the control system 100 that isconnected to the inner core 34 via cable 45 (as illustrated in FIG. 1).The feedback control system 68 allows the temperature at eachtemperature sensor 20 to be monitored and allows the output power of theenergy source 70 to be adjusted accordingly. A physician can, ifdesired, override the closed or open loop system.

In an example embodiment, the feedback control system 68 includes anenergy source 70, power circuits 72 and a power calculation device 74that is coupled to the ultrasound radiating members 40. A temperaturemeasurement device 76 is coupled to the temperature sensors 20 in thetubular body 12. A processing unit 78 is coupled to the powercalculation device 74, the power circuits 72 and a user interface anddisplay 80.

In an example method of operation, the temperature at each temperaturesensor 20 is determined by the temperature measurement device 76. Theprocessing unit 78 receives each determined temperature from thetemperature measurement device 76. The determined temperature can thenbe displayed to the user at the user interface and display 80.

In an example embodiment, the processing unit 78 includes logic forgenerating a temperature control signal. The temperature control signalis proportional to the difference between the measured temperature and adesired temperature. The desired temperature can be determined by theuser (as set at the user interface and display 80) or can be presetwithin the processing unit 78.

In such embodiments, the temperature control signal is received by thepower circuits 72. The power circuits 72 are configured to adjust thepower level, voltage, phase and/or current of the electrical energysupplied to the ultrasound radiating members 40 from the energy source70. For example, when the temperature control signal is above aparticular level, the power supplied to a particular group of ultrasoundradiating members 40 is reduced in response to that temperature controlsignal. Similarly, when the temperature control signal is below aparticular level, the power supplied to a particular group of ultrasoundradiating members 40 is increased in response to that temperaturecontrol signal. After each power adjustment, the processing unit 78monitors the temperature sensors 20 and produces another temperaturecontrol signal which is received by the power circuits 72.

In an example embodiment, the processing unit 78 optionally includessafety control logic. The safety control logic detects when thetemperature at a temperature sensor 20 exceeds a safety threshold. Inthis case, the processing unit 78 can be configured to provide atemperature control signal which causes the power circuits 72 to stopthe delivery of energy from the energy source 70 to that particulargroup of ultrasound radiating members 40.

Because, in certain embodiments, the ultrasound radiating members 40 aremobile relative to the temperature sensors 20, it can be unclear whichgroup of ultrasound radiating members 40 should have a power, voltage,phase and/or current level adjustment. Consequently, each group ofultrasound radiating members 40 can be identically adjusted in certainembodiments. For example, in a modified embodiment, the power, voltage,phase, and/or current supplied to each group of ultrasound radiatingmembers 40 is adjusted in response to the temperature sensor 20 whichindicates the highest temperature. Making voltage, phase and/or currentadjustments in response to the temperature sensed by the temperaturesensor 20 indicating the highest temperature can reduce overheating ofthe treatment site.

The processing unit 78 can also be configured to receive a power signalfrom the power calculation device 74. The power signal can be used todetermine the power being received by each group of ultrasound radiatingmembers 40. The determined power can then be displayed to the user onthe user interface and display 80.

As described above, the feedback control system 68 can be configured tomaintain tissue adjacent to the energy delivery section 18 below adesired temperature. For example, in certain applications, tissue at thetreatment site is to have a temperature increase of less than or equalto approximately 6° C. As described above, the ultrasound radiatingmembers 40 can be electrically connected such that each group ofultrasound radiating members 40 generates an independent output. Incertain embodiments, the output from the power circuit maintains aselected energy for each group of ultrasound radiating members 40 for aselected length of time.

The processing unit 78 can comprise a digital or analog controller, suchas a computer with software. In embodiments wherein the processing unit78 is a computer, the computer can include a central processing unit(“CPU”) coupled through a system bus. In such embodiments, the userinterface and display 80 can include a mouse, a keyboard, a disk drive,a display monitor, a nonvolatile memory system, and/or other computercomponents. In an example embodiment, program memory and/or data memoryis also coupled to the bus.

In another embodiment, in lieu of the series of power adjustmentsdescribed above, a profile of the power to be delivered to each group ofultrasound radiating members 40 can be incorporated into the processingunit 78, such that a preset amount of ultrasonic energy to be deliveredis pre-profiled. In such embodiments, the power delivered to each groupof ultrasound radiating members 40 is provided according to the presetprofiles.

In an example embodiment, the ultrasound radiating members are operatedin a pulsed mode. For example, in one embodiment, the time average powersupplied to the ultrasound radiating members is between about 0.1 wattsand about 2 watts. In another embodiment, the time average powersupplied to the ultrasound radiating members is between about 0.5 wattsand about 1.5 watts. In yet another embodiment, the time average powersupplied to the ultrasound radiating members is approximately 0.6 wattsor approximately 1.2 watts. In an example embodiment, the duty cycle isbetween about 1% and about 50%. In another embodiment, the duty cycle isbetween about 5% and about 25%. In yet another embodiment, the dutycycles is approximately 7.5% or approximately 15%. In an exampleembodiment, the pulse averaged power is between about 0.1 watts andabout 20 watts. In another embodiment, the pulse averaged power isbetween approximately 5 watts and approximately 20 watts. In yet anotherembodiment, the pulse averaged power is approximately 8 watts orapproximately 16 watts. The amplitude during each pulse can be constantor varied.

In an example embodiment, the pulse repetition rate is between about 5Hz and about 150 Hz. In another embodiment, the pulse repetition rate isbetween about 10 Hz and about 50 Hz. In yet another embodiment, thepulse repetition rate is approximately 30 Hz. In an example embodiment,the pulse duration is between about 1 millisecond and about 50milliseconds. In another embodiment, the pulse duration is between about1 millisecond and about 25 milliseconds. In yet another embodiment, thepulse duration is approximately 2.5 milliseconds or approximately 5milliseconds.

For example, in one particular embodiment, the ultrasound radiatingmembers are operated at an average power of approximately 0.6 watts, aduty cycle of approximately 7.5%, a pulse repetition rate ofapproximately 30 Hz, a pulse average electrical power of approximately 8watts and a pulse duration of approximately 2.5 milliseconds.

In an example embodiment, the ultrasound radiating member used with theelectrical parameters described herein has an acoustic efficiencygreater than approximately 50%. In another embodiment, the ultrasoundradiating member used with the electrical parameters described hereinhas an acoustic efficiency greater than approximately 75%. As describedherein, the ultrasound radiating members can be formed in a variety ofshapes, such as, cylindrical (solid or hollow), flat, bar, triangular,and the like. In an example embodiment, the length of the ultrasoundradiating member is between about 0.1 cm and about 0.5 cm, and thethickness or diameter of the ultrasound radiating member is betweenabout 0.02 cm and about 0.2 cm.

FIGS. 11A through 11D illustrate an example method for using certainembodiments of the ultrasonic catheter 10 describe herein. Asillustrated in FIG. 11A, a guidewire 84 similar to a guidewire used intypical angioplasty procedures is directed through a patient's vessels86 to a treatment site 88 that includes a clot 90. The guidewire 84 isoptionally directed through the clot 90. Suitable vessels 86 include,but are not limited to, the large periphery blood vessels of the body.Additionally, as mentioned above, the ultrasonic catheter 10 also hasutility in various imaging applications or in applications for treatingand/or diagnosing other diseases in other body parts.

As illustrated in FIG. 11B, the tubular body 12 is slid over and isadvanced along the guidewire 84, for example using conventionalover-the-guidewire techniques. The tubular body 12 is advanced until theenergy delivery section 18 is positioned at the clot 90. In certainembodiments, radiopaque markers (not shown) are optionally positionedalong the tubular body energy delivery section 18 to aid in thepositioning of the tubular body 12 within the treatment site 88.

As illustrated in FIG. 10C, after the tubular body 12 is delivered tothe treatment site 88, the guidewire 84 is withdrawn from the tubularbody 12 by pulling the guidewire 84 from the proximal region 14 of thecatheter 10 while holding the tubular body 12 stationary. This leavesthe tubular body 12 positioned at the treatment site 88.

As illustrated in FIG. 10D, the inner core 34 is then inserted into thetubular body 12 until the ultrasound assembly 42 is positioned at leastpartially within the energy delivery section 18. In one embodiment, theultrasound assembly 42 can be configured to be positioned at leastpartially within the energy delivery section 18 when the inner core 24abuts the occlusion device at the distal end of the tubular body 12.Once the inner core 34 is positioned in such that the ultrasoundassembly 42 is at least partially within the energy delivery section,the ultrasound assembly 42 is activated to deliver ultrasonic energy tothe clot 90. As described above, in one embodiment, ultrasonic energyhaving a frequency between about 20 kHz and about 20 MHz is delivered tothe treatment site.

In an example embodiment, the ultrasound assembly 42 includes sixtyultrasound radiating members 40 spaced over a length of approximately 30to approximately 50 cm. In such embodiments, the catheter 10 can be usedto treat an elongate clot 90 without requiring moving or repositioningthe catheter 10 during the treatment. However, in modified embodiments,the inner core 34 can be moved or rotated within the tubular body 12during the treatment. Such movement can be accomplished by maneuveringthe proximal hub 37 of the inner core 34 while holding the backend hub33 stationary.

Still referring to FIG. 11D, arrows 48 indicate that a cooling fluid canbe delivered through the cooling fluid lumen 44 and out the distal exitport 29. Likewise, arrows 49 indicate that a therapeutic compound can bedelivered through the fluid delivery lumen 30 and out the fluid deliveryports 58 to the treatment site 88.

The cooling fluid can be delivered before, after, during orintermittently with the delivery of ultrasonic energy. Similarly, thetherapeutic compound can be delivered before, after, during orintermittently with the delivery of ultrasonic energy. Consequently, themethods illustrated in FIGS. 11A through 11D can be performed in avariety of different orders than that described above. In an exampleembodiment, the therapeutic compound and ultrasonic energy are delivereduntil the clot 90 is partially or entirely dissolved. Once the clot 90has been sufficiently dissolved, the tubular body 12 and the inner core34 are withdrawn from the treatment site 88.

Overview of a Small Vessel Ultrasonic Catheter.

Ultrasonic catheters can also be specifically configured to use in thesmall vessels of a patient's vasculature, such as in the vasculature ofa patient's brain. In such a configuration, the catheter is providedwith an energy delivery section having increased flexibility, therebyfacilitating delivery of the catheter through narrow vessels havingsmall radius turns. FIGS. 12A and 12B are cross-sectional views of thedistal region of an example ultrasonic catheter configured for use inthe small vasculature.

Similar to the large vessel ultrasonic catheter described herein, anexample ultrasonic catheter configured for use in small vesselscomprises a multi-component tubular body 202 having a proximal regionand a distal region 206. In such embodiments, the catheter tubular body202 includes an outer sheath 208 that is positioned upon an inner core210. In one embodiment, the outer sheath 208 comprises extruded Pebax®,PTFE, polyetheretherketone (“PEEK”), PE, polyamides, braided polyamidesand/or other similar materials. The outer sheath distal region 206 isadapted for advancement through vessels having a small diameter, such asthose in the vasculature of the brain. In an example embodiment, theouter sheath distal region 206 has an outer diameter between about 2French and about 5 French. In another embodiment, outer sheath distalregion 206 has an outer diameter of about 2.8 French. In one exampleembodiment, the outer sheath 208 has an axial length of approximately150 centimeters.

In a modified embodiment, the outer sheath 208 comprises a braidedtubing formed of, for example, high or low density polyethylenes,urethanes, nylons, and the like. This configuration enhances theflexibility of the tubular body 202. For enhanced maneuverability,especially the ability to be pushed and rotated, the outer sheath 208can be formed with a variable stiffness from the proximal to the distalend. To achieve this, a stiffening member may be included along theproximal end of the tubular body 202.

The inner core 210 defines, at least in part, a delivery lumen 212,which, in an example embodiment, extends longitudinally along thecatheter. The delivery lumen 212 has a distal exit port 214, and ishydraulically connected to a proximal access port (not shown). Similarto the large vessel ultrasonic catheter described herein, the proximalaccess port can be connected to a source of therapeutic compound orcooling fluid that is to be delivered through the delivery lumen 212.

In an example embodiment, the delivery lumen 212 is configured toreceive a guide wire (not shown). In such embodiments, the guidewire hasa diameter of between approximately 0.008 and approximately 0.012inches. In another embodiment, the guidewire has a diameter of about0.010 inches. In an example embodiment, the inner core 210 comprisespolyamide or a similar material which can optionally be braided toincrease the flexibility of the tubular body 202.

Still referring to FIGS. 12A and 12B, the tubular body distal region 206includes an ultrasound radiating member 224. In such embodiments, theultrasound radiating member 224 comprises an ultrasound transducer,which converts, for example, electrical energy into ultrasonic energy.In a modified embodiment, the ultrasonic energy can be generated by anultrasound transducer that is remote from the ultrasound radiatingmember 224 and the ultrasonic energy can be transmitted via, forexample, a wire to the ultrasound radiating member 224.

In the illustrated embodiment, the ultrasound radiating member 224 isconfigured as a hollow cylinder. As such, the inner core 210 extendsthrough the lumen of the ultrasound radiating member 224. The ultrasoundradiating member 224 is secured to the inner core 210 in a suitablemanner, such as using an adhesive. A potting material can also be usedto further secure the ultrasound radiating member 224 to the inner core210.

In other embodiments, the ultrasound radiating member 224 can have adifferent shape. For example, the ultrasound radiating member 224 cantake the form of a solid rod, a disk, a solid rectangle or a thin block.In still other embodiments, the ultrasound radiating member 224 cancomprise a plurality of smaller ultrasound radiating members. Theillustrated configuration advantageously provides enhanced cooling ofthe ultrasound radiating member 224. For example, in one embodiment, atherapeutic compound can be delivered through the delivery lumen 212. Asthe therapeutic compound passes through the lumen of the ultrasoundradiating member 224, the therapeutic compound can advantageously removeexcess heat generated by the ultrasound radiating member 224. In anotherembodiment, a fluid return path can be formed in the region 238 betweenthe outer sheath 208 and the inner core 21 such that coolant from acoolant system can be directed through the region 238.

In an example embodiment, the ultrasound radiating member 224 producesultrasonic energy having a frequency of between about 20 kHz and about20 MHz. In one embodiment, the frequency of the ultrasonic energy isbetween about 500 kHz and about 20 MHz, and in another embodiment thefrequency of the ultrasonic energy is between about 1 MHz and about 3MHz. In yet another embodiment, the ultrasonic energy has a frequency ofabout 3 MHz.

In the illustrated embodiment, ultrasonic energy is generated fromelectrical power supplied to the ultrasound radiating member 224 througha wires 226, 228 that extend through the catheter body 202. The wires226, 228 cab be secured to the inner core 210, lay along the inner core210 and/or extend freely in the region 238 between the inner core 210and the outer sheath 208. In the illustrated configuration, the firstwire 226 is connected to the hollow center of the ultrasound radiatingmember 224, while the second wire 228 is connected to the outerperiphery of the ultrasound radiating member 224. In such embodiments,the ultrasound radiating member 224 comprises a transducer formed of apiezoelectric ceramic oscillator or a similar material.

Still referring to the example embodiment illustrated in FIGS. 12A and12B, the catheter further includes a sleeve 230 that is generallypositioned about the ultrasound radiating member 224. The sleeve 230 iscomprises a material that readily transmits ultrasonic energy. Suitablematerials for the sleeve 230 include, but are not limited to,polyolefins, polyimides, polyester and other materials having arelatively low absorbance of ultrasonic energy. The proximal end of thesleeve 230 can be attached to the outer sheath 208 with an adhesive 232.To improve the bonding of the adhesive 232 to the outer sheath 208, ashoulder 227 or notch can be formed in the outer sheath 208 forattachment of the adhesive 232 thereto. In an example embodiment, theouter sheath 208 and the sleeve 230 have substantially the same outerdiameter.

In a similar manner, the distal end of the sleeve 230 can be attached toa tip 234. As illustrated, the tip 234 is also attached to the distalend of the inner core 210. In an example embodiment, the tip 234 isbetween about 0.5 mm and about 4.0 mm long. In another embodiment, thetip is about 2.0 mm long. In the illustrated example embodiment, the tip234 is rounded in shape to reduce trauma or damage to tissue along theinner wall of a blood vessel or other body structure during advancementof the catheter to a treatment site.

Referring now to the example embodiment illustrated in FIG. 12B, thecatheter includes at least one temperature sensor 236 in the tubularbody distal region 206. The temperature sensor 236 can be positioned onor near the ultrasound radiating member 224. Suitable temperaturesensors include but are not limited to, diodes, thermistors,thermocouples, RTDs and fiber optic temperature sensors that usedthermalchromic liquid crystals. In an example embodiment, thetemperature sensor 236 is operatively connected to a control system viaa control wire that extends through the tubular body 202. As describedabove for the large vessel ultrasonic catheter, the control box includesa feedback control system having the ability to monitor and control thepower, voltage, current and phase supplied to the ultrasound radiatingmember 224. Thus, the temperature along the relevant region of thecatheter can be monitored and controlled for optimal performance.Details of the control box can also be found in U.S. patent applicationSer. No. 10/309,388, filed 3 Dec. 2002, the entire disclosure of whichis hereby incorporated herein by reference.

The small vessel ultrasound catheters disclosed herein can be used toremove an occlusion from a small blood vessel. In an example method ofuse, a guidewire is percutaneously inserted into the patient'svasculature at a suitable insertion site. The guidewire is advancedthrough the vasculature toward a treatment site where the vessel iswholly or partially occluded. The guidewire is then directed at leastpartially through the thrombus.

After advancing the guidewire to the treatment site, the catheter isthen inserted into the vasculature through the insertion site, andadvanced along the guidewire towards the treatment site using, forexample, over-the-guidewire techniques. The catheter is advanced untilthe tubular body distal region 206 is positioned near or in theocclusion. The tubular body distal region 206 optionally includes one ormore radiopaque markers to aid in positioning the catheter at thetreatment site.

After placing the catheter at the treatment site, the guidewire can thenbe withdrawn from the delivery lumen 212. A source of therapeuticcompound, such as a syringe with a Luer fitting, can then be attached tothe proximal access port. This allows the therapeutic compound to bedelivered through the delivery lumen 212 and the distal exit port 214 tothe occlusion.

The ultrasound radiating member 224 can then be activated to generateultrasonic energy. As described above, in an example embodiment, theultrasonic energy has a frequency between about 20 kHz and about 20 MHz.In one embodiment, the frequency of the ultrasonic energy is betweenabout 500 kHz and about 20 MHz, and in another embodiment the frequencyof the ultrasonic energy is between about 1 MHz and about 3 MHz. In yetanother embodiment, the ultrasonic energy has a frequency of about 3MHz. The therapeutic compound and ultrasound energy can be applied untilthe occlusion is partially or entirely dissolved. Once the occlusion hasbeen sufficiently dissolved, the catheter can be withdrawn from thetreatment site.

Further information on example methods of use, as well as on modifiedsmall vessel catheter constructions, are available in U.S. patentapplication Ser. No. 10/309,417, filed 3 Dec. 2002, the entiredisclosure of which is hereby incorporated herein by reference.

Treatment of Vascular Occlusions Using Ultrasonic Energy andMicrobubbles.

In certain embodiments, the therapeutic compound delivered to thetreatment site includes a plurality of microbubbles having, for example,a gas formed therein. A therapeutic compound containing microbubbles isreferred to herein as a “microbubble compound” or “microbubbletherapeutic compound”. In an example embodiment, the microbubbles areformed by entrapping microspheres of gas into a therapeutic compound. Inone embodiment, this is accomplished by agitating the therapeuticcompound while blowing a gas into the therapeutic compound. In anotherembodiment, this is accomplished by exposing the therapeutic compound toultrasonic energy with a sonicator under a gaseous atmosphere whilevibrating the therapeutic compound. Other techniques for forming themicrobubbles are used in other embodiments. Example gases that areusable to form the microbubbles include, but are not limited to, air,oxygen, carbon dioxide, octafluoropropane, and inert gases.

In one embodiment, the microbubble therapeutic compound wholly orpartially comprises a suspension of perflutren lipid microspheres, suchas that available under the brand name DEFINITY®, which is availablefrom Bristol-Myers Squibb Medical Imaging, Inc. (New York, N.Y.). Insuch embodiments, the microbubbles comprise octafluoropropane (C₃F₈)encapsulated in an outer lipid shell. In one embodiment, the microbubbletherapeutic compound is optionally diluted in a phosphate bufferedsaline solution.

A hemacytometer, microscope and digital camera are usable to viewconsistent volumes of a microbubble therapeutic compound, therebyenabling quantitative determination of certain properties of themicrobubbles in the therapeutic compound. Such properties includequantity of microbubbles per unit volume and microbubble sizedistribution. In certain applications, such properties are affected byfactors such as (a) the temperature at which the microbubble therapeuticcompound is stored; (b) the physical handling of the microbubbletherapeutic compound by vibrating for a time period or allowing tosettle for a time period; (c) the handling of the microbubbletherapeutic compound with a syringe; (d) the exposure of the microbubbletherapeutic compound to the atmosphere; and (e) the dilution of themicrobubble therapeutic compound.

The microbubble therapeutic compound preferably includes betweenapproximately 4×10⁶ and approximately 12×10⁹ microbubbles per milliliterof liquid, more preferably between about 8×10⁶ and about 10×10⁹microbubbles per milliliter of liquid, and most preferably approximately4×10⁷ microbubbles per milliliter of liquid. In one embodiment, thequantity of microbubbles per unit volume of carrier fluid is manipulatedby diluting the microbubble therapeutic compound in a neutral solution,such as a phosphate buffered saline solution.

The microbubbles preferably have an average diameter that is preferablybetween approximately 0.01 μm and approximately 100 μm and morepreferably between approximately 0.4 μm and approximately 6 μm. Themicrobubble therapeutic compound is passed through the delivery lumen ata flow rate that is preferably between about 1 mL per hour and about 120mL per hour, that is more preferably between about 10 mL per hour andabout 100 mL per hour, and that is most preferably between about 18 mLper hour and about 22 mL per hour. Optionally, a syringe pump is used toregulate the infusion of microbubble therapeutic compound into thedelivery lumen. Other microbubble and delivery parameters are used inother embodiments. For example, in one embodiment pulsed ultrasonicenergy having a frequency between about 1 MHz and about 3 MHz(preferably about 1.7 MHz) delivered for between about 15 minutes andabout 45 minutes (preferably about 30 minutes) advantageously provides aspatial peak negative pressure of between about 1 MPa and about 2 MPa(preferably between about 1.5 MPa and 2 MPa), which is sufficient togenerate therapeutically beneficial cavitation at the treatment site.

In some embodiments, the volume of microbubble therapeutic compounddelivered to the catheter treatment zone (also referred to as the “bolusvolume”) depends on the size of the treatment zone. Table A lists theapproximate bolus volume for a treatment zone of a particular size. Thevalues listed in the table are approximate and can be varied at thephysician's discretion. For example, in some embodiments, the bolusvolume corresponding to a treatment zone of approximately 6 cm isbetween approximately 0.5 and 2.5 mL; for a treatment zone ofapproximately 12 cm the bolus volume is between approximately 2 and 4mL; for a treatment zone of approximately 18 cm the bolus volume isbetween approximately 3 and 5 mL; for a treatment zone of approximately24 cm the bolus volume is between approximately 5 and 7 mL; for atreatment zone of approximately 30 cm the bolus volume is betweenapproximately 6 and 8 mL; for a treatment zone of approximately 40 cmthe bolus volume is between approximately 8 and 11 mL; and for atreatment zone of approximately 50 cm the bolus volume is betweenapproximately 11 and 13 mL.

TABLE A Bolus Volume Bolus Volume Treatment Zone (example) (preferredrange)  6 cm 1.4 mL 0.5 mL-2.5 mL 12 cm 2.9 mL 2.0 mL-4.0 mL 18 cm 4.3mL 3.0 mL-5.0 mL 24 cm 5.8 mL 5.0 mL-7.0 mL 30 cm 7.2 mL 6.0 mL-8.0 mL40 cm 9.6 mL  8.0 mL-11.0 mL 50 cm  12 mL 11.0 mL-13.0 mL

Optionally, the fluid in which the microbubbles are suspended does nothave therapeutic properties itself, but is merely configured to deliverthe microbubbles to the treatment site. Alternatively, the fluid inwhich the microbubbles are suspended has therapeutic properties, such asa solution containing rtPA that is diluted to a concentration of, forexample, between about 2500 IU mL⁻¹ and about 7500 IU mL⁻¹. In otherembodiments, some microbubbles can be infused with a drug withtherapeutic properties. The drug infused microbubbles may also entrap agas in addition to the drug. In some embodiments, the entrapped gasitself may be a drug with therapeutic properties, such as nitric oxide.These microbubbles can be delivered to the treatment site and be used todeliver drug to the treatment site when the bubble pops. Drug infusedmicrobubbles can be mixed with non-drug infused microbubbles and bedelivered as a mixture. Popping of the drug infused microbubbles, suchas through a cavitation process, can be facilitated or enhanced withultrasound treatment.

In certain configurations, delivering a microbubble therapeutic compoundthrough an optional syringe pump, through a catheter fluid deliverylumen, and past an activated ultrasound radiating member will reduce (a)the concentration of microbubbles delivered to the treatment site,and/or (b) the average size of the microbubbles delivered to thetreatment site. Therefore, in an example embodiment the ultrasoundradiating member is not activated until all or a portion of themicrobubble therapeutic compound is delivered to the treatment site.

In other embodiments, a first portion of the microbubble therapeuticcompound is delivered to the treatment site before the ultrasoundradiating member is activated, and a second portion of the microbubbletherapeutic compound is delivered to the treatment site after theultrasound radiating member is activated. In still other embodiments,the microbubble therapeutic compound is delivered to the treatment siteonly when the ultrasound radiating member is active. In embodimentswherein a microbubble therapeutic compound and ultrasonic energy aredelivered to the treatment simultaneously, additional measures are takento provide a sufficient density of microbubbles at the treatment site.Examples of such additional measures include using a microbubbletherapeutic compound with an increased microbubble density, andproviding an insulating chamber around the fluid delivery lumen, asdescribed in greater detail below.

In an example embodiment, the efficacy of an ultrasound-based vascularocclusion treatment is enhanced by the presence of microbubbles at thetreatment site. In one embodiment, the microbubbles act as a nucleus forcavitation, thus allowing cavitation to be induced at lower levels ofultrasonic energy. Therefore, it is possible to increase the treatmentefficacy as a result of cavitation without increasing the amount ofultrasonic energy delivered to the treatment site. In certainembodiments, cavitation also promotes more effective diffusion andpenetration of the therapeutic compound into surrounding tissues, suchas the clot material. This effect is often referred to as“microstreaming”. Furthermore, in some embodiments, the “microjet”mechanical agitation caused by motion of the microbubbles is effectivein mechanically breaking up clot material.

While certain vascular treatments are enhanced by the presence ofmicrobubbles at the treatment site, certain intravascular catheterfeatures have an adverse affect on the delivery of a microbubbletherapeutic compound to an intravascular treatment site. For example, incertain configurations microbubbles have a tendency to accumulate in andclog the fluid delivery ports 58 and the fluid delivery lumens 30,especially in embodiments wherein a temperature sensor 20 is positionedtherein. For example, see the example embodiment illustrated in FIG. 8.This effect is particularly problematic in embodiments wherein the sizeof the microbubbles are not significantly smaller than the size of thefluid delivery ports 58. For example, as described herein, in certainembodiments the microbubbles have an average diameter of betweenapproximately 0.01 μm and approximately 100 μm, and the fluid deliveryports 58 have an average diameter between about 28 μm and about 48 μm.Additionally, in certain embodiments a portion of the microbubbles aredestroyed as a result of the infusion pressure used to deliver thetherapeutic compound through the delivery lumens and/the or shearstresses generated by fluid flow through the delivery lumens. The extentto which these structural catheter features affect the concentration ofmicrobubbles that is ultimately delivered to the treatment site dependson several factors, including the flow rate of microbubble therapeuticcompound through the delivery lumen and the concentration of themicrobubble therapeutic compound delivered through the delivery lumen.

Furthermore, the microbubbles in a microbubble therapeutic compoundoccasionally cavitate and/or burst when exposed to ultrasonic energy,regardless of whether that exposure occurs inside or outside the fluiddelivery lumens of the ultrasonic catheter. When such cavitation occurswithin the fluid delivery lumens of the ultrasonic catheter, this notonly reduces the quantity of microbubbles delivered to the treatmentsite, but it also increases the risk of damaging the fluid deliverylumens due to the energy released as a result of the cavitation. Theextent to which cavitation occurs within the fluid delivery lumens of anultrasonic catheter depends on factors such as the flow rate ofmicrobubbles through the lumen (which is proportional to the time themicrobubbles are exposed to ultrasonic energy), the concentration ofmicrobubbles in the therapeutic compound (which is proportional to theamount of acoustic shielding for the microbubbles) and the number ofactive ultrasound radiating members in the catheter (which isproportional to the amount of ultrasonic energy delivered to the lumen).In an example embodiment, the ultrasonic catheter is configured suchthat the presence of a microbubble therapeutic compound in the deliverylumens does not substantially effect the operation of the ultrasoundradiating members.

Therefore, in certain embodiments, the catheter design and/or thetreatment techniques are modified to reduce cavitation within thecatheter fluid delivery lumens and/or to preserve the quantity ofmicrobubbles delivered to the treatment site. Consequently, in certainembodiments, such modifications advantageously improve the efficacy of amicrobubble-based vascular occlusion treatment.

For example, in an embodiment that is particularly advantageous for usewith an ultrasonic catheter having a cylindrical ultrasound radiatingmember (such as that illustrated in FIGS. 12A and 12B) an insulatingchamber is used to reduce the amount of ultrasonic energy that isdelivered into the catheter fluid delivery lumen. Specifically, aninsulating chamber is positioned between the ultrasound radiating memberand the delivery lumen. In such embodiments, the insulating chamber isfilled with a material that does not efficiently transmit ultrasonicenergy, thereby reducing the amount of ultrasonic energy reaching thefluid delivery lumen. Example materials that are put into the insulatingchamber include, but are not limited to, air, nitrogen and oxygen. In amodified embodiment, an evacuated chamber is used.

FIG. 13 illustrates an example embodiment of an ultrasound catheterhaving an ultrasound radiating member 320 separated from a deliverylumen 338 by an insulating chamber 330. The ultrasound radiating member320 is offset from the delivery lumen 338 using spacers 316 and supportmembers 318. Other insulating chamber configurations are used in otherembodiments. Additional information on using insulating chambers tospatially direct ultrasonic energy is provided in U.S. Pat. Nos.6,582,392 and 6,676,626, the entire disclosure of which is incorporatedherein by reference.

In another embodiment, a microbubble therapeutic compound is infusedintra-arterially or intravenously to the treatment site before theultrasound radiating members are activated. Therefore, once theultrasound radiating members begin to generate ultrasonic energy, themicrobubble therapeutic compound is already at the treatment site. Themicrobubble therapeutic compound is delivered using the same catheterthat is used to the deliver the ultrasonic energy in some embodiments.The microbubble therapeutic compound is delivered using a differentcatheter than that used to deliver the ultrasonic energy in otherembodiments. The microbubble therapeutic compound is delivered to thetreatment site via the general vascular circulation in still otherembodiments. Regardless of how the initial delivery of microbubbles tothe treatment site is accomplished, ultrasonic energy is delivered tothe treatment site after the delivery of microbubbles has occurred. Atherapeutic compound or a cooling fluid is optionally delivered to thetreatment site during ultrasonic energy delivery, thereby enhancing thetreatment efficacy and/or helping to cool the ultrasound radiatingmembers. In one embodiment, a microbubble therapeutic compound isdelivered to the treatment site to supplement the concentration ofmicrobubbles provided at the treatment site provided by the initialdelivery of microbubbles. Optionally, a cooling element is used to helpmoderate the temperature of the treatment site.

In a modified embodiment, a microbubble therapeutic compound isdelivered to the treatment site intermittently with ultrasonic energy.In one such embodiment, the microbubble therapeutic compound isdelivered without ultrasonic energy during a first treatment phase.Subsequently, delivery of the microbubble therapeutic compound is pausedand ultrasonic energy is delivered to the treatment site during a secondtreatment phase. Optionally, the first and second treatment phases arealternately repeated several times. The duration of the first and secondphases are each on the order of approximately a few minutes. Forexample, in one embodiment, the first and second phases each have aduration that is preferably between about 1 minute and about 20 minutes,that is more preferably between about 2 minutes and about 7 minutes, andthat is most preferably between about 3 minutes and about 4 minutes.Optionally, the first and second treatment phases have differentdurations.

Alternating the delivery of microbubble therapeutic compound andultrasonic energy advantageously reduces the amount of cavitation thatoccurs within the catheter fluid delivery lumen or lumens. In otherembodiments, the therapeutic compound delivered to the treatment site isalternated between a therapeutic compound that contains microbubbles anda therapeutic compound that does not contain microbubbles. In suchembodiments, the phases wherein ultrasonic energy is deliveredcorrespond to the phases during in which the therapeutic compound thatdoes not contain microbubbles is delivered.

In one embodiment, the microbubble therapeutic compound is injecteddirectly into a vascular obstruction at the treatment site. A schematicillustration of this embodiment is provided in FIG. 14. Specifically,FIG. 14 illustrates a catheter 400 having a distal end that ispositioned within an occlusion 410 in a patient's vasculature 420. Amicrobubble therapeutic compound 430 has been infused into the occlusion410 from the catheter 400. Once the microbubble therapeutic compound hasbeen sufficiently infused, one or more ultrasound radiating members 440mounted within the catheter 400 is energized, thereby deliveringultrasonic energy to the occlusion 410 and the infused microbubbletherapeutic compound 430. The catheter 400 is optionally repositionedduring the treatment to direct additional ultrasonic energy into alarger portion of the occlusion 410 and the infused microbubbletherapeutic compound 430. In such embodiments, ultrasonic energy isapplied to the microbubbles suspended within the occlusion, therebycausing mechanical agitation and/or cavitation of the microbubbles. Themechanical agitation and/or cavitation of the microbubbles assistsfaster enzyme mediated lysis of the clot and/or generates microholesthat increase the clot surface area available to interact with lysingenzymes.

As described herein, in certain embodiments control circuitry is used toselectively activate certain ultrasound radiating members in thecatheter. In certain embodiments, such control circuitry is also used toselectively activate an infusion pump that controls delivery of amicrobubble therapeutic compound through the catheter fluid deliverylumens. Such embodiments advantageously allow the ultrasonic energy andthe microbubble therapeutic compound to be separately delivered duringdistinct periods of the treatment. In an example embodiment, the controlcircuitry is capable of controlling a wide variety of infusion pumpconfigurations, such as a rotating syringe pump, a peristaltic pump, oranother pump that is capable of developing pressure differentialsslowly. In a modified embodiment, the pump housing and/or the reservoirfrom which the microbubble therapeutic compound is drawn in agitated orrotated to prevent settling of the microbubbles during the course of thetreatment.

An example system that includes certain of these features isschematically illustrated in FIG. 15. Specifically, FIG. 15 illustratesan intravascular catheter 500 that is capable of receiving a fluid froma first reservoir 502 that contains a microbubble therapeutic compound.The catheter 500 is also capable of receiving an ultrasound controlsignal from an ultrasound signal generator 504. Controller 506 isconfigured to control the ultrasound signal generator 504 and aninfusion pump 508 that is coupled to the first reservoir 502. Thecontroller 506 is also optionally configured to control an agitator 510that is capable of vibrating, rotating, or otherwise agitating the firstreservoir 502. As described herein, this configuration is advantageouslycapable of using a single controller 506 to alternatively causeultrasonic energy and a microbubble therapeutic compound to be deliveredfrom the catheter 500 to the treatment site. The controller 506 isoptionally configured to periodically agitate the first reservoir 502 topreserve the concentration of microbubbles in the microbubbletherapeutic compound held therein.

In modified embodiments, the intravascular catheter 500 is optionallyalso capable of receiving a fluid from a second reservoir 512 thatcontains a therapeutic compound that does not include microbubbles. Insuch embodiments, the infusion pump 508 is also coupled to the secondreservoir, as is configured such that the controller 506 can be used toindependently control delivery of fluids from the first reservoir 502and the second reservoir 512 to the catheter 500. This configurationadvantageously allows the controller 506 to be used to alternatedelivery of a microbubble therapeutic compound and a therapeuticcompound that does not include microbubbles to the catheter 500.

Regardless of the specific delivery techniques, use of a microbubbletherapeutic compound provides enhanced clot weight reduction in certaincircumstances. For example, in one application a 45±19% clot weightreduction enhancement was provided by supplementing an rtPa-containingtherapeutic compound with ultrasonic energy. However, a 88±25% clotreduction enhancement was provided by supplementing an rtPA-containingtherapeutic compound with ultrasonic energy and a microbubble-containingsolution. As used herein, “clot reduction enhancement” is defined as theclot weight reduction as compared before and after treatment.

Treatment of Vascular Occlusions Using Cavitation Promoting Surface.

Disclosed herein are methods for enhancing the beneficial effect ofultrasonic energy at an intravascular treatment site by promotingcavitation at the treatment site. Aside from manipulating the acousticparameters of the ultrasonic energy, other techniques for promotingcavitation at the treatment site include supplying an ultrasoundcontrast agent to the treatment site and/or using an ultrasound catheterthat includes a cavitation promoting surface. Use of such techniquesreduces the acoustic pressure amplitude required to initiate cavitation,and therefore allows lower levels of ultrasonic energy to be deliveredto the treatment site from the ultrasound assembly. This providesseveral advantages, such as prolonging the life of an ultrasoundradiating member and reducing the likelihood of causing thermal damageto the treatment site. While cavitation is used to enhance the deliveryand/or effect of a therapeutic compound in certain embodiments,cavitation promotes clot dissolution even in the absence of atherapeutic compound. Indeed, in the context of treating a vascularocclusion, the beneficial effect of cavitation in the absence of atherapeutic compound is often greater than the beneficial effect of atherapeutic compound alone.

Because cavitation promoting surfaces and ultrasound contrast agents areindependently capable of inducing cavitation at an intravasculartreatment site, in certain embodiments cavitation is induced at anintravascular treatment site using a cavitation promoting surface, butwithout using an ultrasound contrast agent. Such embodimentsadvantageously simplify the treatment procedure by eliminating the needto monitor the concentration of the ultrasound contrast agent at thetreatment site, reduce the treatment cost, and reduce the risk ofsystemic complications caused by the ultrasound contrast agent. In otherembodiments, cavitation is induced at an intravascular treatment siteusing a ultrasound contrast agent, but without using a cavitationpromoting surface. Such embodiments advantageously are usable withconventional ultrasound catheters that have not been modified to includethe cavitation promoting surface. In still other embodiments, both acavitation promoting surface and an ultrasound contrast agent are usedto enhance cavitation at the treatment site. Regardless of whether aultrasound contrast agent, a cavitation promoting surface, or both, areused to promote cavitation, the generation of free microbubbles at thetreatment site is optionally manipulated by adjusting the frequency,peak pressure and duration of ultrasonic energy delivered to thetreatment site.

Techniques for using a therapeutic compound that includes microbubbles(that is, a “microbubble therapeutic compound”) to enhance the effect ofa vascular occlusion treatment have been disclosed herein. In oneapplication a catheter with a cavitation promoting surface is used todeliver a microbubble therapeutic compound to an internal portion of avascular occlusion, as opposed to the fluid medium surrounding theocclusion. This is particularly important in view of the observationthat the viscoelastic properties of the surrounding medium affect howmicrobubbles respond to ultrasonic energy.

In some embodiments, a cavitation promoting surface is obtained bypatterning a catheter surface with an ablative laser. For example, anexcimer laser with mask projection technique can be used to preciselypattern features onto the catheter surface. In some embodiments, thefeatures are holes that are generally circular in shape. In otherembodiments, the holes are oval, rectangular, triangular or anothergeometrical shape. In some embodiments, the features are approximately15 μm in diameter and/or depth. In other embodiments, the features arebetween approximately 1 and 100 μm in diameter and/or depth. In someembodiments, the features can be separated by approximately 25 μm. Inother embodiments, the features can be separately by a distance betweenapproximately 1 and 100 μm. FIGS. 16A and 16B illustrate an example of acatheter surface 3000 having a laser patterned cavitation promotingsurface 3010. As illustrated in FIGS. 16A and 16B, the cavitationpromoting surface 3010 comprises holes 3020 that are formed on a portionof the catheter surface 3000. In one embodiment, the holes 3020 do notextend through the catheter body, but instead are formed as surfacefeatures on the exterior catheter surface 3000. The cavitation promotingsurface 3010 can be formed on the portion of the catheter surface 3000that is proximate the ultrasound radiating members and/or the energydelivery section of the catheter.

In other embodiments, a cavitation promoting surface is obtained by gritblasting a catheter surface with an angular media. For example, onesuitable angular media is a powder of aluminum oxide particles having anaverage diameter of approximately 25 μm. Aluminum oxide and othersimilar angular media are dry media, which advantageously facilitatecleaning of the catheter surface after the roughening treatment isperformed. In other embodiments, the angular media has a diameterbetween approximately 1 and 100 μm.

In other embodiments, a cavitation promoting surface is obtained byscoring a catheter surface. In some embodiments, the depth and/or widthof the scoring is between approximately 1 and 100 μm. In someembodiments, the scoring is a single continuous spiral that winds aroundthe catheter surface. In other embodiments, the scoring is formed frommultiple intersecting spirals that form a cross-hatched pattern on thecatheter surface. In other embodiments, the scoring is formed byparallel and non-intersecting scores.

In other embodiments, a cavitation promoting surface is obtained byetching a catheter surface. In some embodiments, the etching is donewith chemicals, plasma or laser. An etch mask can be applied to thecatheter surface to limit etching to appropriate areas of the cathetersurface. In some embodiments, the etching results in features similar tothose produced by laser ablation, scoring or grit blasting.

In some embodiments, a hydrophobic coating is applied to the cathetersurface either before or after the cavitation promoting surface isformed as described herein. In some embodiments, the hydrophobic coatingis formed, for example, from parylene. In some embodiments, applicationof the hydrophobic coating lowers the surface energy between blood andthe cavitation promoting surface allowing for easier bubble liberation.

In other embodiments, a cavitation promoting surface is obtained bycoating a catheter surface with a superhydrophobic material withnanoscale porous structures. For example, one such coating materialconsists of polypropylene with an appropriate solvent, such as p-xylene,and the appropriate nonsolvent, such as methyl ethyl ketone, which isused to precipitate the dissolved polypropylene out of the solvent.After precipitation, the solvent and nonsolvent is removed byevaporation, leaving a film of porous material. In some embodiments, theporous structures provide gas entrapment sites for cavitation nucleiwhile the superhydrophobic properties reduce the surface energy allowingfor easier bubble liberation.

In other embodiments, a cavitation promoting surface is obtained byattaching a porous ceramic, resin, polymer or metal material to acatheter surface. The porous structure acts as a source of entrapped gasfor cavitation nuclei.

Treatment of Vascular Occlusions Using Stable and/or InertialCavitation.

Although this disclosure is not limited by theory, it is believed thatultrasonic energy accelerates enzymatic fibrinolysis through non-thermalmechanisms by increasing transport of drug molecules into the clot.Mechanical effects of ultrasonic energy such as streaming, radiationforce and cavitation have the ability to influence drug transport.Acoustic cavitation is generally acknowledged as playing a significantrole in ultrasound-accelerated fibrinolysis. The addition of ultrasoundcontrast agents has been shown to increase the effectiveness ofultrasound-accelerated enzymatic fibrinolysis. Mechanisms related toboth inertial cavitation (for example, intense localized stresses andmicro-jets) and stable cavitation (for example, cavitationmicro-streaming and bubble translation) are believed to be responsiblefor the enhanced drug transport and lysis.

In certain embodiments, the type of cavitation activity occurring at thetreatment site is determined by analyzing frequency components in thescattered acoustic emissions from the treatment site. For examplesubharmonic emission at half the driving frequency, which is acharacteristic of stable nonlinear bubble oscillation, provides ageneral indicator for stable cavitation activity. Broadband noise, whichis manifested as an elevation in the signal amplitude between theharmonic peaks in the fast Fourier transform (“FFT”) magnitude spectrum,provides a general indicator for inertial cavitation activity. In theabsence of cavitation, only the fundamental ultrasound drive signal andits harmonics are present, aside from broadband electrical backgroundnoise.

In certain embodiments, the broadband noise in a particular signal isquantified by integrating the “inter-peak” noise amplitude NA between 4and 10 MHz. Other frequency spectra are used in other embodiments. Toreference the noise amplitude to a non-cavitating “baseline” signal—suchas that obtained in degassed (<36% of saturation), 0.2 μm filteredwater—a relative noise enhancement RNE was calculated as the increase innoise amplitude relative to the average baseline noise amplitude <BNA>for n recorded baseline “bursts” of the hydrophone signal:

${R\; N\; E} = \left\lbrack \frac{{N\; A} - {\langle{B\; N\; A}\rangle}}{\langle{B\; N\; A}\rangle} \right\rbrack$

A true rise in broadband noise over baseline due to inertial cavitationis identified by setting a detection threshold. For example, in oneapplication the noise enhancement threshold NET is defined as therelative noise enhancement corresponding to 4 times the standarddeviation of the baseline noise amplitude SD{BNA} for n recordedbaseline bursts:

${N\; E\; T} = \left\lbrack \frac{4 \times {SD}\left\{ {B\; N\; A} \right\}}{\langle{B\; N\; A}\rangle} \right\rbrack$

By searching digitized “snapshots” of noise activity for instances inwhich the relative noise enhancement crossed the noise enhancementthreshold, a total number of ultrasound bursts containing inertialcavitation (“IC count”) is determined. Additionally, the maximumrelative noise enhancement detected in a snapshot max{RNE} compiled asan average from m independent snapshots is optionally compared betweentreatments, thereby enabling further statistical analysis.

In certain embodiments, subharmonic emission in a particular signal isidentified by the presence of a subharmonic peak in the FFT magnitudespectrum at one half of the fundamental frequency. To quantify thesubharmonic content in a recorded burst, the FFT magnitude spectrum iscomputed and the magnitude at the subharmonic frequency was taken as thesubharmonic amplitude SA. To reference the subharmonic amplitude to anon-cavitating baseline signal—such as that obtained in degassed (<36%of saturation), 0.2 μm filtered water—the relative subharmonicenhancement RSE is calculated as the increase in subharmonic amplituderelative to the average baseline subharmonic amplitude <BSA> for nrecorded baseline bursts:

${R\; S\; E} = \left\lbrack \frac{{S\; A} - {\langle{B\; S\; A}\rangle}}{\langle{B\; S\; A}\rangle} \right\rbrack$

Processed in this way, each digitized burst yields a single measure ofthe relative subharmonic enhancement, for which it is possible to plotas a function of time over the duration of the snapshot. For a givensnapshot, the subharmonic quantities are averaged over the n bursts toyield the average subharmonic enhancement <RSE>. The average value of<RSE> is optionally compiled from m independent snapshots and comparedbetween treatment groups, thereby enabling further statistical analysis.

A plot illustrating RNE as a function of time during a 3.33-secondsnapshot for an example 30-minute ultrasound exposure within a clot isillustrated in FIG. 17. A plot illustrating RSE as a function of timeduring a 3.33-second snapshot for an example ultrasound exposure withina clot is illustrated in FIG. 18. Data from four treatment protocols areillustrated in FIGS. 17 and 18: therapeutic compound and ultrasonicenergy (D+US); therapeutic compound, ultrasonic energy, and microbubbles(D+US+MB); therapeutic compound, ultrasonic energy, and microbubblesthat were previously exposed to ultrasound (D+US+MB(pre)); andultrasonic energy and microbubbles (US+MB).

As illustrated in FIGS. 17 and 18, in the absence of microbubbles(D+US), both RNE and RSE remained at baseline. When microbubbles werepresent, cavitation signals were high and were substantially identicalfor the two protocols in which the microbubbles were not pre-exposed toultrasonic energy (D+US+MB and US+MB). RNE increased rapidly to a peakvalue within about 0.1 seconds, decreased toward baseline, crossed belowthe detection threshold (NET≈0.24) at about 0.4 seconds, and settled tobaseline by about 1.0 seconds. Similarly, RSE increased to a peak valuewithin about 0.1 seconds. However, RSE did not settle back to baseline,but instead remained at a slightly elevated value during the remainderof the snapshot. For the protocol in which microbubbles were pre-exposedto ultrasonic energy (D+US+MB(pre)), broadband noise and subharmonicactivity were reduced compared to the other microbubble-based protocols.Specifically, elevation in RNE was observed in generally the firstultrasound burst, which immediately dropped to baseline by the nextburst. On the other hand, RSE remained at a low, steady amplitudeslightly above baseline.

The cavitation signal quantities per snapshot measured at various timesthroughout the 30-minute exposure are shown in FIGS. 19A and 19B(max{RNE}) and FIGS. 20A and 20B (<RSE>). In the absence of microbubbles(D+US), max{RNE} remained below the detection threshold for the entire30-minute exposure, and <RSE> remained at baseline. For the snapshottaken at time zero, max{RNE} for each of the microbubble-based protocolswas significantly greater than that for the non-microbubble (D+US)protocol (p<0.033). The max{RNE} for both the (D+US+MB) and the (US+MB)protocols were significantly greater than that for the (D+US+MB(pre))protocol (p<0.001). For the remainder of the 30-minute exposure,max{RNE} for the microbubble-based protocols showed no significantdifference from the non-microbubble (D+US) protocol. For allmicrobubble-based protocols <RSE> was significantly greater than thatfor the non-microbubble (D+US) protocol during both the snapshot at timezero (p<0.001) and during the remainder of the 30-minute exposure(p<0.010).

Table B lists the total number of IC counts observed for the differenttreatment protocols. In accordance with the max{RNE} trends shown inFIGS. 19A and 19B, IC counts were only observed during the initialsnapshot in the 30-minute exposure. The number of counts was greatestfor the two protocols in which microbubbles were not pre-exposed toultrasound (D+US+MB and US+MB). In the absence of microbubbles (D+US),two IC counts were recorded.

TABLE B Time D + D + D + US + US + Window US US + MB MB (pre) MB TotalNumber of 0 min 1000 1000 1000 1000 Bursts Analyzed 1-30 min 6000 60006000 6000 Total Number of 0 min 2 103 5 111 IC Counts 1-30 min 0 0 0 0

In the absence of microbubbles, pulsed ultrasonic energy significantlyaccelerates rtPA-induced fibrinolysis in certain applications. In suchapplications, thermal mechanisms are not believed to have played a rolein lysis enhancement. The minimal degree of heating observed isconsidered to be insufficient to account for the increased lysis.Cavitation signals were either not detected (subharmonic amplituderemained at baseline) or were negligible (only two IC counts) in thecorresponding radiated acoustic signal, suggesting that the observedlysis enhancement in the absence of microbubbles was due tonon-cavitation mechanical effects of the ultrasonic energy.

In embodiments wherein microbubbles are dispersed within the clot, lysisenhancement due to ultrasonic energy increased significantly, confirmingthe synergistic effect of microbubbles and therapeutic compound.Inertial cavitation, observed as broadband noise in the acoustic signal,was present only at the start of the ultrasound exposure, anddisappeared completely in less than one second. Subharmonic emission, anindicator for stable cavitation activity, was greatest at the start ofthe exposure, subsequently decreased in amplitude, yet persisted for theremainder of the 30-minute treatment. Without being limited by theory,the limited duration of inertial cavitation is explained by liberatedmicrobubbles yielding sub-resonant bubbles (for example, bubbles smallerthan resonance size at 1.7 MHz) that break up upon collapse, therebyforming very small bubbles that are quickly driven to dissolution by thecompressive force of surface tension.

In the presence of microbubbles alone, ultrasound exposure resulted inno measurable lysis, indicating that mechanical disruption (for example,fragmentation) of the clot was not a contributing mechanism for lysis.This lack of effect is not surprising because of the limited duration ofinertial cavitation observed. Optionally, the microbubbles arereplenished, or the acoustic parameters (such as acoustic pressureamplitude, pulse length, or duty cycle) are modified to increase thepersistence and quantity of inertial cavitation to an extent wheremechanical effects alone become important.

In embodiments wherein microbubbles were pre-exposed to ultrasound priorto therapeutic compound delivery, the cavitation activity that occurredat the start of the treatment was significantly reduced compared to theother microbubble-based protocols. In particular, inertial cavitationwas substantially eliminated: only the first ultrasound burst containedbroadband noise. Without being limited by theory, a possible explanationfor this result is that all of the candidate sub-resonant bubbles were“used up” in the pre-exposure and thus were not available to nucleateinertial cavitation when the therapeutic compound was present. Thelow-amplitude subharmonic emission, however, was still present duringthe 30-minute exposure and at the same magnitude as in the otherprotocols with microbubbles. Without being limited by theory, thisresult suggests the presence of super-resonant bubbles. Super-resonantbubbles are large bubbles that are less influenced by surface tension,that do not dissolve as quickly as smaller bubble, and that are held inplace by the dense fibrin matrix of the clot. Lysis enhancement in suchembodiments was substantially the same as that obtained for treatmentsin which microbubbles were not pre-exposed to ultrasound.

Without being limited by theory, these results suggest that theincreased lysis enhancement in the presence of microbubbles wascorrelated with the subharmonic emission that occurred throughout the30-minute treatment, and that the brief inertial cavitation thatoccurred at the beginning of the exposure was inconsequential. Thissuggests that mechanisms related to stable cavitation (for example,steady micro-streaming) rather than inertial cavitation (for example,mechanical disruption and transient micro-jets) were responsible for theincreased lysis in the presence of microbubbles. In embodiments whereinsustained inertial cavitation is achieved using modified acousticparameters, it is possible to obtain an even greater degree of lysisenhancement.

In certain embodiments the additional lysis enhancement due tomicrobubbles is correlated to the presence of the subharmonic emission,thus identifying an important role for stable cavitation inmicrobubble-enhanced ultrasound-accelerated fibrinolysis. Mechanismsrelated to stable cavitation, such as steady micro-streaming, enhancefibrinolysis by promoting local mass transfer and thus the rate ofpenetration of the therapeutic compound into the clot matrix. Thus, incertain embodiments inertial cavitation is optionally reduced oreliminated without adversely effecting the enhancement ofultrasound-accelerated fibrinolysis in the presence of microbubbles.Thus, in such embodiments it is possible to avoid the safety risksassociated with inertial cavitation (for example, tissue hemorrhage andhemolysis) while still enjoying the lysis-enhancing effect ofmicrobubbles by choosing ultrasound exposure parameters to promotestable cavitation while minimizing or eliminating inertial cavitation.

As described herein, subharmonic emission was used as a generalindicator for stable cavitation. In certain embodiments, other types ofstable bubble activity, including oscillations that occur below thepressure threshold for subharmonic emission, occur simultaneously andare also responsible for lysis enhancement. However, surface waves onthe bubble wall, which have been associated with subharmonic emissions,are effective in generating micro-streaming flows around bubblesundergoing repetitive large amplitude motion.

SCOPE OF THE INVENTION

While the foregoing detailed description discloses several embodimentsof the present invention, it should be understood that this disclosureis illustrative only and is not limiting of the present invention. Itshould be appreciated that the specific configurations and operationsdisclosed can differ from those described above, and that the methodsdescribed herein can be used in contexts other than treatment ofvascular occlusions.

1. A method of manufacturing an ultrasound catheter, the methodcomprising: providing an elongate catheter body having a distal region,a proximal region opposite the distal region, and an exterior surface;positioning an ultrasound radiating member within the distal region ofthe elongate catheter body; forming a fluid delivery lumen within theelongate catheter body, wherein the fluid delivery lumen extends betweenthe proximal region and the distal region; providing a fluid deliveryport in the distal region of the elongate catheter body, the fluiddelivery port being hydraulically connected to the fluid delivery lumen;and forming a plurality of surface features on the exterior surface ofthe catheter body distal region using an ablative laser.
 2. The methodof claim 1, wherein the plurality of surface features comprise aplurality of holes that do not extend through the catheter body.
 3. Themethod of claim 1, wherein the ablative laser is an excimer laser. 4.The method of claim 1, wherein the plurality of surface features areformed using a mask projection technique.
 5. The method of claim 1,wherein: the plurality of surface features comprise a plurality of holesthat do not extend through the catheter body; and wherein the pluralityof holes have a diameter between approximately 1 μm and approximately100 μm.
 6. The method of claim 1, wherein: the plurality of surfacefeatures comprise a plurality of holes that do not extend through thecatheter body; and wherein the plurality of holes are separated fromeach other by an average distance that is between approximately 1 μm andapproximately 100 μm.
 7. The method of claim 1, wherein the plurality ofsurface features are formed adjacent to the ultrasound radiating member.8. The method of claim 1, wherein the plurality of surface features offormed adjacent to the fluid delivery port.
 9. An apparatus comprising:an elongate, hollow catheter body having a distal region, a proximalregion opposite the distal region, and an exterior surface; anultrasound radiating member positioned with the distal region of thecatheter body; a fluid delivery lumen extending between the proximalregion and the distal region of the catheter body; and a plurality ofholes formed in the exterior surface of the catheter body distal region.10. The apparatus of claim 9, further comprising a fluid delivery portformed in the distal region of the elongate catheter body, the fluiddelivery port being hydraulically connected to the fluid delivery lumen.11. The apparatus of claim 9, wherein the plurality of holes do notextend through the catheter body.
 12. The apparatus of claim 9, whereinthe plurality of holes are formed using an ablative laser.
 13. Theapparatus of claim 9, wherein the plurality of holes have a diameterbetween approximately 1 μm and approximately 100 μm.
 14. The apparatusof claim 9, wherein the plurality of holes are separated from each otherby an average distance that is between approximately 1 μm andapproximately 100 μm.
 15. The apparatus of claim 9, wherein theplurality of holes are positioned adjacent to the ultrasound radiatingmember.
 16. The apparatus of claim 9, further comprising a plurality ofultrasound radiating members positioned within the distal region of thecatheter body.